The present invention provides compositions and methods for inducing analgesia, in particular, for treating opiate intolerance associated with opiate analgesics.
Therapeutic analgesic doses of morphine, as well as other opiate analgesics, provide pain relief that is often accompanied by a number of unpleasant side effects, such as nausea, vomiting, and constipation. Use of higher doses of narcotics in surgery to supplement hypnotic anesthesia, for example morphine, fentanyl, sufentanyl, alfentanyl or remifentanyl, may cause unwanted bradycardia and hypotension that can complicate the surgical procedures or the recovery. In the postoperative setting, emesis is reduced but not completely controlled by ondansetron, granisetron, dolagetron, metaclopramide and other serotonin receptor antagonist based anti-emetics. Emesis can still be a problem when patients are sensitive to opiate side effects and opiates are used as part of the surgical anesthesia, or used postoperatively to control pain. An agent to selectively block opiate intolerance with minimal side effects would improve medical treatment, either used by itself, or in combination with opiates, or in combination with existing anti-emetic drugs in treating opiate intolerance and post surgical emesis.
Studies with quaternized opiate antagonists, such as N-methylnalorphine, indicate that the quaternized opiate antagonists do not penetrate the blood-brain barrier into the brain. The analgesic effects of opiates are mediated by receptors in the central nervous system, while the opiate receptors that mediate many unwanted opiate side effects lie outside the blood brain barrier. Thus, quaternized opiate antagonists can antagonize many unwanted side effects of opiates without reducing analgesia. For example, studies of N-methylnalorphine, which is a mixture of the R and S isomers, have shown that it antagonizes opiate induced constipation, bradycardia, and emesis at doses that do not alter the ability of opiate agonists to reduce pain.
The S and R isomers of N-methylnalorphine, which are alternatively referred to as the axial and equatorial isomers, have been described as opiate antagonists in the literature, but to date the isomers have only been tested separately in in vitro studies or by a test involving direct injection onto brain. The in vitro studies used receptor binding and isolated tissues to define the range and nature of the receptor interactions, characterizing both isomers as opiate antagonists with reduced potency relative to nalorphine. In addition to a predominant opiate antagonist effect, the S isomer was characterized as having very weak agonist properties in guinea pig ileum but not other tissues with mu receptors, such as the vas deferens (Kobylecki et al., (1982) J. Med. Chem., 25, 1280-1286). The authors speculated that the agonist effects were not mediated by mu opiate receptors.
The two isomers of N-methylnalorphine have also been compared by directly injecting them into the brain of mice. Both isomers antagonized morphine analgesia in the range of 0.25 to 0.5 ug per mouse brain (lorio et. al., (1984) Eur. J. Med. Chem., 19, 11-16). The weak agonist properties of the S isomer were also apparent at very high doses. Both agents were able to antagonize morphine analgesia by injection into brain. The meaning of this study for medical use of these substances is difficult to determine, however, since quaternized agents do not enter the brain, nor do they antagonize morphine analgesia if given by conventional medical routes of administration. Indeed, it would not be desirable to administer these compounds directly to the central nervous system, thereby antagonizing the analgesic effects of opiates.
As far as the present inventors are aware, there have been no published studies that suggest therapeutically significant differences in the pharmacology of the R and S isomers of N-methylnalorphine in intact mammals using medically appropriate routes of administration.
It has now surprisingly been found that the essentially pure R isomer of N-methylnalorphine provides a superior treatment to antagonize or prevent opiate induced side effects in mammals, and to have a significantly reduced ability to produce side effects such as nausea, vomiting, and ataxia, when compared with the S isomer or a mixture of R and S N-methylnalorphine.
Accordingly, one aspect of the present invention is a method of treating opiate intolerance in a subject in need of such treatment, comprising administering to the subject a treatment effective amount of R N-methylnalorphine or a pharmaceutically acceptable salt thereof. The opiate intolerance may be manifested by nausea, vomiting, constipation, hypotension, bradycardia, and/or pruritus, or other side-effects associates with opiates, as are known in the art. The active compound can be administered by any route but is preferably administered by intravenous, subcutaneous or intramuscular injection. Administration by a patient-controlled injection device is also preferred. More preferably, the opiate analgesic and the active compound are co-administered in a single composition using a patient-controlled injection device. As a further alternate embodiment, the active compound can be administered concurrently with other therapeutic agents, e.g., an anti-emetic compound.
As a further aspect, the present invention provides a method of inducing analgesia in a subject in need of such treatment, comprising administering to the subject an opiate analgesic in an amount effective to induce analgesia in the subject concurrently with R N-methylnalorphine or a pharmaceutically acceptable salt thereof in an amount effective to treat opiate intolerance. Preferably, concurrent administration of the active compound does not substantially reduce opiate analgesia in the subject.
As yet a further aspect, the present invention provides a composition, comprising, in combination in a pharmaceutically acceptable carrier, an opiate analgesic in an amount effective to induce analgesia in a subject and R N-methylnalorphine or a pharmaceutically acceptable salt thereof in an amount effective to treat opiate intolerance. In particular embodiments, the composition comprises other therapeutic compound(s), e.g., an anti-emetic compound.
These and other aspects of the present invention are provided in more detail in the description of the invention below.